In different areas of technology it is desirable to make use of a thin sheet of material which has an array of regularly spaced, very small holes therein. For example, such might be used in the manufacture of various electronic components. Thin sheets which have one or more holes in them could also be used in the formation of components used in ink jet printers or fuel injectors. A more direct application of such a pore array is as a filter. The pore size and pore density could be adjusted to wide range of filter applications. Alternatively, liquid formulations containing a drug could be moved through such a porous member to create an aerosol for inhalation.
One of the gentlest and most acceptable methods of administering an agent to a patient is via aerosol. Aerosol therapy can be accomplished by aerosolization of a formulation (e.g., a drug formulation or diagnostic agent formulation) and administration to the patient, for example via inhalation. The aerosol can be used to treat lung tissue locally and/or be absorbed into the circulatory system to deliver the drug systemically. Where the formulation contains a diagnostic agent, the formulation can be used for diagnosis of, for example, conditions and diseases associated with pulmonary dysfunction.
In general, aerosolized particles for respiratory delivery have a diameter of 12 micrometers or less. However, the preferred particle size varies with the site targeted (e.g., delivery targeted to the bronchi, bronchia, bronchioles, alveoli, or circulatory system). For example, topical lung treatment can be accomplished with particles having a diameter in the range of 1.0 to 12.0 micrometers. Effective systemic treatment requires particles having a smaller diameter, generally in the range of 0.5 to 6.0 micrometers, while effective ocular treatment is adequate with particles having a diameter of 15 micrometers or greater, generally in the range of 15-100 micrometers.
U.S. Pat. Nos. 5,544,646, 5,709,202, 5,497,763, 5,544,646, 5,718,222, 5,660,166, 5,823,178 and 5,829,435 describe devices and methods useful in the generation of aerosols suitable for drug delivery. These devices generate fine, uniform aerosols by passing a formulation through a nozzle array having micrometer-scale pores as may be formed, for example, by LASER ablation.
Pore arrays having such small features can be difficult and costly to manufacture. Additionally, the pores must be of high quality and uniformity where they are to be used (1) in manufacturing electronic components; (2) in filter materials; (3) in ink jet printers; (4) in fuel injectors; and (5) to create aerosols for delivering therapeutic agents to patients in order to insure that the patients consistently receive the therapeutically required dose. Consequently, there is a need for a fabrication method and an inspection method which can rapidly manufacture and analyze porous samples of small dimensions to determine various parameters including pore size and pore density, and with the ability to adjust such parameters to produce a pore array having high quality and uniform pores. In the preferred embodiment, the manufacture and analysis are done simultaneously by monitoring the beam as it drills through the part.
In most cases it is desirable to increase the rate at which a process can produce output. Although this invention was developed in part by an evaluation of LASER drilling microscopic holes, nothing in the motivation, analysis, or applications necessarily limits the scope to drilling, micromachining, or even to LASER processing.
Presently, LASERs are used to drill holes in a variety of materials for a variety of purposes. In particular, ultraviolet LASERs are used to drill micro-vias in multi-layer electronic circuits and in polymer films for such applications as ink-jet printer nozzles (cf U.S. Pat. No. 4,508,749) and aerosol drug delivery. This process is frequently implemented using an excimer LASER and a mask and projection system to drill multiple holes at once.
There are several disadvantages to this approach. Excimer LASERs generally have intensive energy and utility (cooling and venting) requirements, and the incoherent nature of the beam makes mask and projection the most viable method of multiplexing the beam. The use of a masking system usually involves discarding much of the LASER energy, and in many cases of LASER hole drilling as much as 99% of the LASER power is stopped by the mask and not used for the drilling process. In addition, the non-uniform output beam generally seen with excimer LASERs usually requires the use of homogenizers, and even then this technology has uniformity limitations.
It is difficult to drill holes with exit diameters less than 1 micrometer using the process as described in U.S. Pat. No. 4,508,749. An improvement to this process was introduced in U.S. Pat. No. 6,624,885 and U.S. Publication No. US-2004-0070754-A1, published Apr. 15, 2004 that allows smaller holes to be drilled. It is difficult to achieve good beam homogeneity across excimer LASER beams, and beam power variations can also be introduced when multiplexing other types of LASERs. Thus, this control method faces limitations in feature-to-feature (hole-to-hole) uniformity within multiple feature arrays machined in a single operation.
Although the feedback control method of U.S. Pat. No. 6,624,885 can be applied to a process that drills only one hole at a time, this seriously limits the production speed of such a process due to the requirement to step the target or beam from hole to hole, and then allow for settling time.
The process with feedback control implemented might be sped up in one of at least three ways without fundamentally changing the process. The rate of LASER pulsing can be increased, the time to step from one feature to the next can be decreased, or the number of features machined at once can be increased with individual feedback applied to each of the features. Although excimer LASERs are limited to a few hundred pulses per second, some solid-state UV LASERs (Lambda Physik Gator, Coherent Avia) can pulse as many as 100,000 times per second or more. This could result in speeding the process up by more than 100 times. However, it also reduces the time between pulses from more than 1 millisecond to only 10 microseconds. Some LASER drilling processes produce a small cloud of plasma with each LASER pulse and it may be that this plasma cloud, if not allowed time to dissipate, will modify the drilling process by attenuating or reflecting the LASER beam.
It may be more desirable to maintain the rate at which pulses reach each feature but increase the number of features drilled at the same time. However, as this discussion indicated, spatially multiplexing the beam can result in non-uniformity between the individual features within the multiplicity, and it can be difficult to control the characteristics of the individual features. It is possible to use a detector with spatial resolution to monitor the progress of the process for each feature. However, for the nozzles used in aerosol drug delivery, this may require independently controlling hundreds of LASER beams based on the feedback from a detector with hundreds or thousands of elements. In addition, machining a large array at once may in itself lead to plasma shielding effects. Despite these difficulties, a dynamic beam-splitter based on an acousto-optic modulator driven at many frequencies at once could split the beam into dozens or hundreds of beams, and the individual beams could be turned on or off (based on information from a feedback detector) by modifying the multi-frequency drive signal. This method could be used independently or in combination with the other methods disclosed and described here.
A large improvement in fabrication time can be achieved by rapidly switching a single beam from one feature to another. Using standard staging to move a target piece from one feature to another can require on the order of 100 ms to move and settle, and as a result, machining a part such as a nozzle array containing hundreds of nozzles can take on the order of a minute to complete. This time can be reduced to a few seconds by using galvanometer mirrors, or galvos. Acousto-optic modulators (AOMs) are capable of moving a beam from one position to another in approximately 1 micro-second, and can be used to reduce the amount of time moving between features to a negligible fraction of the fabrication time. Two dimensional arrays of features can be fabricated by using two galvos, two AOMs, or in a preferred embodiment, one AOM and one galvo. In addition, the progress of the individual holes can be monitored with a detector and the drilling process can be adjusted or terminated based on this monitoring. For example, the detector can be place behind the part being modified, and when the beam has created a through hole, a property of the LASER light transmitted through the piece, for example its intensity, can be measured, and the process can be modified or terminated based on this measurement. The detector can have a temporally resolved response so that the properties of each sequential pulse can be determined, and then the process can be adjusted or terminated for that hole when appropriate.
The number of features being machined can also be increased by multiplexing the drilling operation in time, directing sequential LASER pulses at the multiplicity of features to be machined. For instance, a series of 100 pulses from a 100,000 kHz pulse train can be directed sequentially at a series of 100 holes to be drilled, and then the process can be repeated. In this example, each individual hole receives pulses at only 1 kHz, allowing time for the plasma cloud to dissipate before the next pulse. An advantage of this is that the beam can be scanned continuously, rather than in step and repeat fashion, eliminating the time delays associated with acceleration, deceleration, and settling. In addition, the progress of the individual holes can be monitored with a detector and the drilling process can be adjusted or terminated for each hole individually. The detector can have a temporally resolved response so that the properties of each sequential pulse can be determined and associated with the feature at which that pulse was directed, and then the process can be adjusted or terminated for that hole when appropriate. Alternatively, the detector can have a spatially resolved response so that the progress of the drilling at each location can be determined. In either case, once a hole is determined to be substantially complete, the pulses that would continue to drill that hole can be omitted from the LASER pulse train.
Implementing this control scheme requires: a method of scanning the LASER beam (that is, directing sequential LASER pulses at sequential features), a method of detecting the progress of drilling on the individual holes, and a controller that analyzes the detection, synchronizes the pulses, scanning and detection, and a controller to generate and omit pulses and control the scanning of the beam as needed.
A number of types of high-speed scanning systems exist. LASER printers typically use a spinning polygonal mirror to scan a LASER beam across the print copy thousands of times per second. Many LASER machining systems use mirrors mounted on high-speed galvanometers to scan the machining LASER beam across the work piece at similar frequencies. Acousto-optic modulators, already used for spectrometers, LASER Q-switches, and some LASER scanning systems can achieve even higher frequencies.
Aspects of spatially multiplexing LASER beams used for processing is referred to in U.S. Pat. No. 6,625,181 which uses a fixed beamsplitter configuration, beam modulation after beamsplitting without feedback.